EP3366324A1 - Produit et procédé de traitement de tissus bioprothétiques - Google Patents

Produit et procédé de traitement de tissus bioprothétiques Download PDF

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EP3366324A1
EP3366324A1 EP17157490.8A EP17157490A EP3366324A1 EP 3366324 A1 EP3366324 A1 EP 3366324A1 EP 17157490 A EP17157490 A EP 17157490A EP 3366324 A1 EP3366324 A1 EP 3366324A1
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Prior art keywords
cyclodextrin
ethanol
treatment
tissues
calcification
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German (de)
English (en)
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Enrico Pasquino
Marcio Scorsin
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Epygon SAS
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Epygon SAS
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Priority to EP17157490.8A priority Critical patent/EP3366324A1/fr
Priority to BR112019017295-5A priority patent/BR112019017295A2/pt
Priority to KR1020197027202A priority patent/KR20190121326A/ko
Priority to JP2019565610A priority patent/JP2020508193A/ja
Priority to EP17829940.0A priority patent/EP3585451B1/fr
Priority to CA3054091A priority patent/CA3054091A1/fr
Priority to SG11201907695WA priority patent/SG11201907695WA/en
Priority to PCT/EP2017/080977 priority patent/WO2018153525A1/fr
Priority to AU2017400910A priority patent/AU2017400910B2/en
Priority to US16/487,117 priority patent/US11660375B2/en
Priority to ES17829940T priority patent/ES2936112T3/es
Priority to RU2019127523A priority patent/RU2019127523A/ru
Priority to CN201780089366.2A priority patent/CN110494171A/zh
Publication of EP3366324A1 publication Critical patent/EP3366324A1/fr
Priority to IL26886519A priority patent/IL268865A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3625—Vascular tissue, e.g. heart valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/02—Treatment of implants to prevent calcification or mineralisation in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves

Definitions

  • the present invention relates to the treatment of bioprosthetic tissues, in particular of biological tissues that are used in cardiovascular bioprostheses.
  • Calcification is one of the major causes of the failure of bioprosthetic heart valves derived from Glutaraldehyde-pretreated bovine pericardium or porcine aortic valves.1-3. Such pre-treatment are disclosed for instance in US patent 5,931,969 (Baxter ). The mechanism of this type of pathologic calcification is incompletely understood. In animal models, it has been shown that initial calcium nucleation sites are cell membranes, the nucleus, and intracellular organelles, such as the mitochondria of devitalized cells. With increasing duration of implantation, cell-associated calcific deposits increase in size and number. Direct collagen calcification in cusps and elastin calcification in the aortic wall subsequently occur. Various host factors, such as the young age of a recipient, and implant factors, such as Glutaraldehyde fixation, also aggravate calcification events.
  • Bio tissues are currently largely used for manufacturing bioprostheses, mainly in cardiovascular field, for long-term implants.
  • the biological tissues used for cardiovascular bioprostheses are represented by xenografts (e.g. native valves, pericardial sacs, blood vessels, tendons, etc.7) mainly originated from bovine or porcine tissues.
  • xenografts e.g. native valves, pericardial sacs, blood vessels, tendons, etc.
  • bovine or porcine tissues bovine or porcine tissues.
  • cross-link a chemical reaction aimed at bonding the collagen and elastin fibers together and stabilizing the extracellular matrix.
  • the cross-link treatment has also the advantage to increase the mechanical properties of the tissues in order to grant its necessary long-term durability. This last aspect is of particular interest for the pericardial tissues or for the cusps of native animal valves used to assemble heart valve bioprostheses replacing the aortic, mitral, tricuspid or pulmonary diseased human valves.
  • Glutaraldehyde cross-link or fixation reaction promotes dystrophic calcification because of the chemical process between free aldehyde groups of Glutaraldehyde, phospholipids, fatty acids and cholesterol and residual antigenicity of the biological tissues 1,2,3 .
  • the main anticalcification strategies are aimed to extract lipids 4 or to neutralize toxic aldehyde residuals 5 .
  • Glutaraldehyde-fixed xenografts have cellular/humoral rejection and calcify secondarily 3 . Tissue valve calcification is also initiated primarily within residual cells that have been devitalized 1 .
  • the Cyclodextrins are cyclic natural oligosaccharides constituted by 6, 7 or 8 monomers of D-(+) Glucopyranose joined together with a ⁇ ,1-4 glucosidal bond and closed resulting in a conical-toroidal shape ( Figure 1 ).
  • the three most common forms are ⁇ -CD (6 units), ß-CD (7 units) and ⁇ -CD (8 units).
  • the second advantage of inclusion complex formation consists in greatly modifying the properties of the molecule of interest (more precisely "drugs” in our case) in many ways such as improving drug stability, bioavailability, oral administration and drug interaction with biological membranes or cells. This latter advantage can easily explain the reason why Cyclodextrins have appealed so much attention and have been marketed worldwide in many industry areas from food, cosmetics, environmental engineering to chemical, pharmaceutical production and development.
  • the ⁇ -Cyclodextrin ( Figure 3 ) can be used in pharmaceutical field thanks to their absence of toxicity when orally administered. In this field they are often used thanks to their host capacity to mask the distasteful flavor of some drugs, to covert liquid compounds in solid ones and furthermore to improve the bioavailability profile of many drugs especially thanks to the increased water solubility.
  • the natural ⁇ -Cyclodextrins can't be used for parenteral administration because they are nephrotoxic, however the hydroxypropyl derivatives (HP ⁇ -CD) of these Cyclodextrins (commercially known as Cavasol®) and the ⁇ -Cyclodextrins can be used for parenteral administration because they don't show any toxicity and allow the formulation of drugs totally insoluble in water ( Figure 2 ).
  • Methylated ⁇ -Cyclodextrin (M ⁇ -Cyclodextrin) are not suitable for parenteral administration even the somewhat lipophilic randomly M ⁇ -Cyclodextrin does not readily permeate lipophilic membranes, although it interacts more readily with membranes than the hydrophilic Cyclodextrin derivatives.
  • the Sulfobutyl Ether 7 ⁇ -Cyclodextrin (SBE 7 ⁇ -CD) 7 is another ⁇ -Cyclodextrin that has been more recently synthetized.
  • SBE 7 ⁇ -CD is a highly water-soluble derivative of ⁇ -Cyclodextrin that is commercially available as Captisol®.
  • Cyclodextrins When administered orally, Cyclodextrins are generally considered safe as they do not cross the intestinal barrier, however, for the same Cyclodextrin the route of administration can modify its toxicity as demonstrated for native ⁇ -Cyclodextrin, which exhibits a limited toxicity after oral administration in animals as the acceptable daily intake has been limited to 5 mg/kg of body weight by the International Program on Chemical Safety (IPCS; WHO Food Additives Series 32), whereas parenteral or subcutaneous injections at higher doses get nephrotoxic affecting proximal tubules.
  • IPCS International Program on Chemical Safety
  • the mode of clearance of Cyclodextrins from the organisms also depends on the route of administration. For example, HP ⁇ -Cyclodextrin is mainly eliminated by glomerular filtration in the kidneys and excreted into urine after intravenous injection in rats, whereas oral administration is mainly excreted through faeces in rats and dogs.
  • methylated ⁇ -Cyclodextrin derivatives such as the randomly methylated ⁇ -Cyclodextrins (RAME ⁇ and KLEPTOSE® CRYSME ⁇ displaying 12.6 and four methyl groups, respectively), the HP- ⁇ -Cyclodextrin with hydroxypropyl groups randomly substituted onto the ⁇ -Cyclodextrin molecule, and also the sulfobutylether-7- ⁇ -Cyclodextrin (SBE7- ⁇ -Cyclodextrin) that are currently evaluated for the treatment of neurodegenerative disorders and atherosclerosis.
  • RAME ⁇ and KLEPTOSE® CRYSME ⁇ displaying 12.6 and four methyl groups, respectively
  • HP- ⁇ -Cyclodextrin with hydroxypropyl groups randomly substituted onto the ⁇ -Cyclodextrin molecule
  • SBE7- ⁇ -Cyclodextrin sulfobutylether-7- ⁇ -Cyclodextrin
  • Cyclodextrins have proven to be very useful in therapy, as they have not shown any hypersensitivity reaction, unlike Sugammadex.
  • This modified Cyclodextrin used in anesthesia to reverse the effect of neurovascular blocking drugs has been involved in allergic response in some patients.
  • the mode of action of Cyclodextrins and their derivatives can occur in two ways. The first one implies the direct biological action of the Cyclodextrins on cell membranes whereas the second one is rather indirect using the encapsulation potentiality of Cyclodextrins as drug carriers.
  • Cyclodextrins The direct action of the Cyclodextrins on cells consists in extracting lipids (cholesterol and phospholipids) as well as some proteins from cell membranes modifying the molecular composition of the lipid bilayers and thus their properties ( Figure 5 ). It has been described that ⁇ -Cyclodextrin removes phospholipids, ⁇ -Cyclodextrin extracts phospholipids and cholesterol whereas ⁇ -Cyclodextrin is less lipid-selective than other Cyclodextrins.
  • Cyclodextrins are widely used as drug delivery carrier via nasal mucosae, pulmonary-, ocular-, dermal-, intestinal- and brain-barriers as these molecules improve delivery and bioavailability of hydrophilic, hydrophobic as well as lipophilic drugs.
  • Cyclodextrins have also been extensively used to improve biocompatibility and enhanced bioavailability, when incorporated into complexes with active drug compounds, thus enhancing drug efficacy.
  • the combination of Cyclodextrins and drug compounds into complexes has been applied in researches for the treatment of atherosclerosis and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.
  • Cyclodextrins can be used as a carrier enabling the selective binding to biomolecules of interest, as reported for example, for cholesterol crystal detection in atherosclerosis.
  • the direct action mode of Cyclodextrins has proven effects on cells, promoting an effective extraction of cholesterol and phospholipids from the lipids raft of cell membranes.
  • the indirect action mode highlights the complexation capacity of Cyclodextrins allowing an even more effective removal of lipids and aldehyde groups.
  • Ethanol has been used, since several years for the treatment of bioprosthetic tissues, such as aortic prosthetic cusps, bovine or porcine pericardial tissue, with the aim to mitigate the process of dystrophic calcification when implanted at long-term.
  • bioprosthetic tissues such as aortic prosthetic cusps, bovine or porcine pericardial tissue
  • the Ethanol has been applied in treatments alone or associated with other substances in general after a cross-link treatment obtained with Glutaraldehyde.
  • the 80.0% Ethanol pretreatment of Glutaraldehyde-crosslinked cusps extracted almost all cholesterol and phospholipids from the cusp samples 10 . It has been hypothesized that phospholipids present in devitalized cells of bioprostheses are an initial source of phosphorus in heart valve calcification due to phosphorester hydrolysis. Other studies also have looked at the connection between cholesterol and calcification in atherosclerotic plaques. It has been shown that cholesterol levels increase progressively with age, correlating directly with the risk of coronary artery disease. Cholesterol also alters calcium transit across cell membranes, cystolic calcium levels, and membrane fluidity in arterial smooth muscle cells. The mechanism by which cholesterol content of the cell membrane correlates with intracellular calcification remains incompletely understood.
  • Ethanol pre-incubation of glutaraldehyde-cross-linked porcine aortic valve bioprostheses is a highly efficacious pre-treatment for preventing calcification of porcine aortic valve cusps in both 60-day rat subdermal implants and sheep mitral valve replacements (150 days).
  • Ethanol was chosen as an anticalcification agent due to its known interference in the cellular metabolism of calcium in bone-line cells as well as in fibroblasts 11,12 .
  • the presence of Ethanol has been shown to break down cellular membranes and disorder acyl chains of phospholipids that affect many cellular activities 13 .
  • Ethanol has been shown to significantly inhibit calcium phosphate nucleation and phase transformations due to its interactions with water 14 .
  • the 80.0% Ethanol pretreatment extracted almost all phospholipids and cholesterol from glutaraldehyde-cross-linked cusps.
  • leaflet samples were analyzed for total lipid and cholesterol content before and after pretreatment.
  • Ethanol with concentration higher than 50.0% was a very efficient extractor of both cholesterol and phospholipids, with nearly complete extraction of both 15 as described in Figure 6 .
  • Membrane-bound phospholipids are considered to be donors of phosphorous in the initial stages of mineralization of bioprosthetic heart valves because of hydrolysis by alkaline phosphatase. Complete removal of phospholipids, which are initial sites of calcification, may partially explain the mechanism of action of Ethanol. However, the results with chloroform-methanol (2:1) treatment demonstrated that this delipidation regimen resulted in the complete extraction of both total cholesterol and phospholipid ( Table 1).
  • the implant duration was extended to 60 days.
  • the controls calcified severely (calcium level, 236 ⁇ 6.1 ⁇ g/mg tissue).
  • the 80.0% Ethanol (pH 7.4 for 24 hours) pretreatment was most effective, with complete inhibition of calcification with the calcium levels comparable to unimplanted bioprosthetic tissue (calcium level, 1.87 ⁇ 0.29 ⁇ g/mg tissue), whereas the 60.0% Ethanol pretreatment was partially effective (calcium level, 28.5 ⁇ 12.0 ⁇ g/mg tissue). Therefore, the 80.0% Ethanol pretreatment was found to be the best condition for preventing leaflet calcification in both the 21- and 60-day rat subdermal models.
  • Table 1 Group Cholesterol Phospholipids Control 13.3 ⁇ 0.4 17.2 ⁇ 0.8 40% Ethanol 13.9 ⁇ 0.7 16.5 ⁇ 1.5 60% Ethanol 0.30 ⁇ 0.05 4.93 ⁇ 1.9 80% Ethanol 0.14 ⁇ 0.02 1.08 ⁇ 0.1
  • the stress strain characteristics of tissues treated with Ethanol were evaluated in aortic valve of porcine tissues cusps 16 . This study compares uniaxial stress strain properties of untreated porcine aortic cusps with those of the Glutaraldehyde treated cusp and those of the Ethanol incubation following Glutaraldehyde.
  • the untreated cusps provided the control (C) while the Glutaraldehyde treated cusps (G) and the Ethanol treated cusps following Glutaraldehyde fixation (G+A) represented the test samples.
  • the Ethanol treatment of Glutaraldehyde tanned tissue not only preserves the tensile strength, which is increased following Glutaraldehyde tanning, but also improves the extensibility in uniaxial testing in circumferential direction. This change in physical characteristics may help in preserving the durability of aortic cusps. The reduction in propensity to calcify and the ability of cuspal tissue to lengthen on stress might help in preventing structural dysfunction. However, it would be appropriate to consider long-term in-vivo durability studies of alcohol treated Glutaraldehyde tanned porcine aortic valves in-vivo to test this hypothesis.
  • the most efficient pretreatments were the combination of Ethanol and surfactant (calcium content: 15.5 ⁇ 6.8 ⁇ g/mg dry tissue after 6 months implantation) or the combination of Ethanol, Ether, and surfactant (13.1 ⁇ 6.2 ⁇ g/mg dry tissue) when compared with surfactant alone (42.9 ⁇ 12.7 ⁇ g/mg dry tissue).
  • Connoly 19 evaluated the post-treatment with sodium borohydride of Ethanol treated porcine aortic cusps.
  • Ethanol pretreatment significantly inhibited calcification compared with controls (13.3 +/- 5.6 versus 119.2 +/- 6.6 Ca ⁇ g/mg tissue; p ⁇ 0.001).
  • sodium borohydride reduction under optimized conditions combined with Ethanol pretreatment optimally reduced calcification (1.16 +/-0.1 Ca ⁇ g/mg; p ⁇ 0.05), whereas levels after sodium cyanoborohydride treatment (23.6 +/- 10.4 Ca ⁇ g/mg) were not significantly different to those after Ethanol alone.
  • Neither reducing agent was effective in inhibiting calcification without Ethanol pretreatment.
  • Ethanol as phospholipids solvent together other with aminoacids to detoxicate the pericardial tissue.
  • Groups of bovine pericardium samples were fixed with 0.5% GA.
  • Urazole and glutamate were used to neutralize the free aldehyde and some solvents (Ethanol with Octanol or Octanediol) to reduce the phospholipid content in the bovine pericardial tissue.
  • Another study 22 was enhanced in order to evaluate the efficiency of aluminum chloride in isolation or associated with Ethanol to prevent calcification and inflammatory reaction with fragments of porcine aortic wall fixed in Glutaraldehyde and subdermally implanted in young rats.
  • Samples of porcine aortic wall were implanted in the subdermal tissue.
  • the specimens were previously subjected to three different methods of treatment: I (glutaraldehyde), II (glutaraldehyde + aluminum), III (glutaraldehyde + ethanol + aluminum).
  • Atomic absorbance spectroscopy showed similar calcium levels for both Groups II and III, but significantly less than in Group I.
  • Treatment with aluminum chloride inhibits calcification of specimens of aortic wall after implantation and reduces inflammatory reaction.
  • the combined use of Ethanol with aluminum chloride is more efficient to inhibit calcification and also to diminish inflammatory reaction.
  • Ethanol is efficient in solubilizing and extracting the lipid raft (cholesterol and phospholipids) from the cell membranes identified as the major responsible for triggering calcification.
  • the best efficiency in term of lipid extraction is obtained at concentrations of 80% but good tissue calcification reduction is already visible with concentrations of 50% 15 .
  • tissue cross-link treatments Triglycidylamine, Genipin, Neomicin
  • post-treatments such as Urazole, Glutamate, Dodium Borohydride, Aluminum Chloride or others, are further reducing the propensity to calcification only when associated to Ethanol.
  • the present invention generally relates to a novel and original use of Cyclodextrin in the treatment of bioprosthetic tissues.
  • Using a Cyclodextrin in this treatment provides bioprosthetic tissues with a long-term mechanical and biological durability, after implant. Such properties are especially critical for heart valve bioprostheses.
  • Cyclodextrins belong to a large family of molecules but for the present invention the most accredited are those of the ⁇ family.
  • the functionalized ⁇ -Cyclodextrins and in particular the HP ⁇ -Cyclodextrin and the SBE ⁇ -Cyclodextrins have been approved for parenteral use. They therefore are expressing all desired chemical action without any damages for the excretory organs even if they are present in traces.
  • Cyclodextrin is used in combination with Ethanol.
  • Cyclodextrin action can be expressed as direct, with primary extraction of lipidic molecules, and indirect with complexation of the lipidic molecules already extracted. It is in this second action mode that Cyclodextrins can complex phospholipids already solubilized by Ethanol.
  • Ethanol and Cyclodextrin can be used simultaneously or separately, in any order.
  • the bioprosthetic tissues are selected for absence of defects and thickness.
  • the selected patches or cusps are submitted to a cross-link process aimed at stabilizing the collagen in order to avoid any immunologic or foreign body tissue response.
  • the cross-link process can be conducted with different molecules, but typically Glutaraldehyde at a concentration ranging between 0.1 % to 1% for a period of 12h to 48h or more is used.
  • the combined delipidation treatment ( Figure 7 ) is performed combining Ethanol at a concentration between 35% and 80% solubilized in a buffered solution at PH 7.4 with 10mM to 200mM of ⁇ -Cyclodextrin for 2h to 24h at a temperature ranging between 25°C and 40°C.
  • the patches are assembled in semi-finished or finished assemblies and then chemically sterilized with an aldehyde based solution eventually added with short chain alcohol molecules.
  • Finished devices are then stored in a solution composed by aldehyde at concentration of 0.1% to 1% and eventually added with short chain alcohol molecules in concentration of 10% to 50%.
  • This pre-implantation rinsing is performed with three aliquots of 500 ml of a solution of ⁇ -Cyclodextrins at a concentration of 10mM to 200 mM at a temperature of 15°C to 30°C.
  • the phospholipid extraction can be performed, after the tissue cross-link, in a disjoined manner in two phases ( Figure 8 ).
  • the phospholipid extraction as described in Figure 8 , can be conducted in inverted way anticipating the exposition to ⁇ -Cyclodextrin followed by Ethanol treatment at the same concentrations and conditions.
  • the combined treatment of Ethanol and ⁇ -Cyclodextrin can be performed anticipating the ⁇ -Cyclodextrin treatment directly on the bioprosthetic tissue before the cross-link procedure ( Figure 9 ) followed by a treatment with an Ethanol solution.
  • the concentration of Ethanol and ⁇ -Cyclodextrin can be the same as described in Figure 7 .
  • This disjoined treatment can be applied in inverted order if needed.
  • the process could include a further detoxification process, based on Cyclodextrins, aimed at removing, in effective way, the residual aldehyde molecules ( Figure 10 ).
  • the aim of this chemical treatment variation is required in order to store the bioprosthesis in a bacteriostatic aldehyde-free storage solution.
  • tissue dehydration in association with a ethylene oxide sterilization. This is done in order to more easily store the bioprostheses avoiding chemical sterilization and their handling especially when they must be collapsed and used in transcatheter procedures.
  • the previous treatment embodiments previously presented, as possible variations, can be associated to the tissue dehydration procedure.
  • a detoxification process is performed with ⁇ -Cyclodextrin is completed with the aim to remove aldehyde molecules from the tissue.
  • a tissue dehydration procedure can be started.
  • This treatment is based on a progressive removal of water from the bioprosthetic tissue obtained with Polyethylene Glycol (e.g. MW 100 to 800) in aqueous solution ranging from 80% to 90%.
  • the treatment is performed at a temperature between 20°C to 50°C for 12h to 48h.
  • short chain alcohols can be added at a concentration of 10% to 20%.
  • the dehydration process is completed with a tissue drying for several hours in a clean environment. It allows a final storage of the bioprostheses in a dry packaging that is submitted to sterilization by means of Ethylene Oxide.
  • All the treatment processes, above described, can be performed on semi-finished assemblies or directly on the final assembled bioprostheses. In this case the processes can be applied as an individual prosthetic treatment.
EP17157490.8A 2017-02-22 2017-02-22 Produit et procédé de traitement de tissus bioprothétiques Withdrawn EP3366324A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EP17157490.8A EP3366324A1 (fr) 2017-02-22 2017-02-22 Produit et procédé de traitement de tissus bioprothétiques
PCT/EP2017/080977 WO2018153525A1 (fr) 2017-02-22 2017-11-30 Produit et procédé pour le traitement de tissus bioprothétiques
AU2017400910A AU2017400910B2 (en) 2017-02-22 2017-11-30 Product and method for the treatment of bioprosthetic tissues
JP2019565610A JP2020508193A (ja) 2017-02-22 2017-11-30 バイオプロテーゼ組織の処理のための生成物および方法
EP17829940.0A EP3585451B1 (fr) 2017-02-22 2017-11-30 Procédé de traitement de tissus bioprothétiques
CA3054091A CA3054091A1 (fr) 2017-02-22 2017-11-30 Produit et procede pour le traitement de tissus bioprothetiques
SG11201907695WA SG11201907695WA (en) 2017-02-22 2017-11-30 Product and method for the treatment of bioprosthetic tissues
BR112019017295-5A BR112019017295A2 (pt) 2017-02-22 2017-11-30 Produto e método para o tratamento de tecidos bioprotéticos
KR1020197027202A KR20190121326A (ko) 2017-02-22 2017-11-30 생체 조직의 치료를 위한 제품 및 방법
US16/487,117 US11660375B2 (en) 2017-02-22 2017-11-30 Product and method for the treatment of bioprosthetic tissues
ES17829940T ES2936112T3 (es) 2017-02-22 2017-11-30 Método para el tratamiento de tejidos bioprotésicos
RU2019127523A RU2019127523A (ru) 2017-02-22 2017-11-30 Продукт и способ для обработки биопротезных тканей
CN201780089366.2A CN110494171A (zh) 2017-02-22 2017-11-30 用于处理生物假体组织的制品和方法
IL26886519A IL268865A (en) 2017-02-22 2019-08-22 Product and method for treating bioprosthetic tissues

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Application Number Priority Date Filing Date Title
EP17157490.8A EP3366324A1 (fr) 2017-02-22 2017-02-22 Produit et procédé de traitement de tissus bioprothétiques

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EP3366324A1 true EP3366324A1 (fr) 2018-08-29

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RU2019127523A3 (fr) 2021-03-23
CN110494171A (zh) 2019-11-22
KR20190121326A (ko) 2019-10-25
SG11201907695WA (en) 2019-09-27
US11660375B2 (en) 2023-05-30
RU2019127523A (ru) 2021-03-23
CA3054091A1 (fr) 2018-08-30
EP3585451B1 (fr) 2022-10-19
AU2017400910B2 (en) 2023-10-12
JP2020508193A (ja) 2020-03-19
AU2017400910A1 (en) 2019-09-12
BR112019017295A2 (pt) 2020-03-31
EP3585451A1 (fr) 2020-01-01

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